GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

St. Petersburg State Pavlov Medical University

Status and phase: Completed; Phase 2; Phase 1

Conditions: Mixed-Lineage Acute Leukemias; Leukemia, Acute Lymphoblastic; Acute Myeloid Leukemia

Treatments: Drug: Bendamustine; Drug: Fludarabine monophosphate; Drug: Busulfan; Procedure: Allogeneic stem cell transplantation

Study type: Interventional

Funder types: Other

Identifiers

NCT02799147

05/16-n

Details and patient eligibility

About

Several groups have demonstrated very low incidence of acute and chronic graft-versus-host disease (GVHD) with post-transplantation cyclophosphamide (PTCy) in haploidentical, unrelated and related allogeneic stem cell transplantation (SCT). Nonetheless for majority of the grafts, except for 10/10 HLA-matched bone marrow, with this type of prophylaxis require concomitant administration of calcineurin inhibitors±MMF, which delays immune reconstitution and development of graft-versus-leukemia (GVL) effect. So, despite reduction of transplant-related mortality, use of PTCy doesn't lead to the reduction of relapse incidence. This is particularly important for relapsed or refractory acute leukemia patients, where, despite all efforts to intensify conditioning regimens, relapses after SCT occur in more than 50% of patients, and long-term survival rarely exceeds 10-20%. In preclinical model of haploidentical SCT the substitution of post-transplantation cyclophosphamide with bendamustine, led to comparable GVHD control, but significantly augmented GVL effect. To test this hypothesis and improve the outcome of allogeneic SCT in refractory acute leukemia patients we initiated a pilot trial with high-dose post-transplantation bendamustine for GVHD prophylaxis. The selection of doses is based on the previous dose-escalation studies. Additional immunosuppression could be added for mismatched grafts.

Enrollment: 27 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Diagnosis: Acute Myeloblastic Leukemia Acute Lymphoblastic Leukemia Mixed-Lineage Acute Leukemias

• Disease, refractory to at list one course of induction chemotherapy or immunotherapy
• More than 5% clonal blasts in the bone marrow or peripheral blood at the time of inclusion
• Signed informed consent
• Matched related, 8-10/10 HLA-matched unrelated or haploidentical donor available. The HLA typing is performed by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1.
• No second tumors
• No severe concurrent illness
• No previous autologous or allogeneic stem cell transplantations

Exclusion criteria

• Karnofsky index <70%
• Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50%
• Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted
• Respiratory distress >grade I
• Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >1.5 upper normal limits
• Creatinine clearance < 60 mL/min
• Uncontrolled bacterial or fungal infection at the time of enrollment, defined by CRP level >70 mg/L or positive procalcitonin in patient with adequate empirical antibacterial and antifungal therapy.
• Requirement for vasopressor support at the time of enrollment
• Pregnancy
• Somatic or psychiatric disorder making the patient unable to sign informed consent

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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27 participants in 3 patient groups

280 mg/m2 bendamustine

Experimental group

Description:

10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3 and +4: Bendamustine 140 mg/m2/day iv.

Treatment:

Procedure: Allogeneic stem cell transplantation

Drug: Busulfan

Drug: Fludarabine monophosphate

Drug: Bendamustine

200 mg/m2 bendamustine

Experimental group

Description:

10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3 and +4: Bendamustine 100 mg/m2/day iv

Treatment:

Procedure: Allogeneic stem cell transplantation

Drug: Busulfan

Drug: Fludarabine monophosphate

Drug: Bendamustine

140 mg/m2 bendamustine

Experimental group

Description:

10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3, +4: Bendamustine 70 mg/m2/day iv.

Treatment:

Procedure: Allogeneic stem cell transplantation

Drug: Busulfan

Drug: Fludarabine monophosphate

Drug: Bendamustine